Integrative Diabetes and Cardiovascular Diseases New Onset Diabetes after Transplant – Risk Factors , Clinical Profile and Outcome

Background: New onset diabetes after transplant (NODAT) remains one among the significant threats to both renal allograft and patient survival. The aim of this study was to analyse the clinical profile and risk factors for NODAT. Methods: This prospective observational study involved patients who underwent renal transplantation in our centre between 2010 and 2015. Results: During the mean follow up period of 18 ± 6 months, incidence of NODAT was 26.6% and the cumulative incidence was highest in the first year after transplant. Recipient age, pre transplant impaired fasting glucose, Hepatitis C virus (HCV) infection, family history of diabetes, tacrolimus, post transplant hypertriglyceridemia and metabolic syndrome were found to be statistically significant risk factors for NODAT. In Cox multivariate regression analysis, age and family history of diabetes were found to be independent risk factors for NODAT. Fasting C-peptide level underlines insulin resistance as predominant mechanism for NODAT in two third of patients. There were higher incidence of urinary tract infection in the NODAT patients. NODAT was found to be an independent risk factor for fungal infection and 10 year cardiovascular risk in the renal recipients. There was no significant impact of NODAT on short term graft and patient survival. Conclusion: Age, pre-transplant fasting blood glucose, family history of diabetes, HCV infection and tacrolimus were found to be the important risk factors, with insulin resistance as the predominant mechanism for NODAT.


Introduction
New onset diabetes after transplant refers to abnormal glucose metabolism detected after transplantation.Starzl et al. [1] was the first to describe diabetes as a complication of kidney transplantation 40 years ago.The term "New Onset Diabetes After Transplant" has replaced the older 'post-transplant diabetes mellitus' to differentiate new onset diabetes from diabetes that was present prior to transplantation.First International consensus guideline on NODAT was published in 2003 [2] with the recommendation to adopt American Diabetes Association (ADA) criteria to define NODAT.Recently, Bloom and Crutchlow [3] introduced the term Transplant Associated Hyperglycemia (TAH) to include the entire spectrum of diabetes and prediabetes encountered after organ transplantation.Large registries have retrospectively concluded that NODAT is a strong, independent predictor of global mortality, graft failure and death-censored graft failure [4].Int Diab Card Dis, 3(1): 35-40 (2018)

Subjects and Methods
Patients who underwent renal transplantation between January 2010 and January 2015 in our department were included in this prospective observational study after getting informed consent.Renal transplant recipients who were diagnosed to have diabetes according to American Diabetes Association (ADA) criteria after transplantation were labelled as study group.Recipients who did not develop diabetes and were on follow-up for at least one year were included in the control group.Transplant recipients who had diabetes before renal transplantation or transient hyperglycaemia while on intravenous steroids or who died in the early post transplant period or lost follow-up before one year were excluded from this study.
Demographics, clinical and laboratory parameters of both the groups were collected.Age, gender, family history of diabetes, pre-transplant Body Mass Index (BMI), type of donor, HCV infection status, details about immunosuppression, anti rejection therapy and associated risk factors like hypertension, post transplant BMI and duration of onset of NODAT were recorded.Presence of post transplant Cytomegalovirus (CMV) infection, urinary tract infection (UTI), tuberculosis (TB), fungal infections and other bacterial infections were also noted.
Blood urea, serum creatinine, fasting and postprandial blood sugar, lipid profile were measured peridically as per KDIGO guidelines for renal transplantation.Fasting C-peptide level was measured in the study group by chemiluminescence assay (manufactured by SIEMENS), β cell function and insulin sensitivity were calculated using Homeostatic model assessment (HOMA) version 2.2 (Online calculator).Framingham 10 year cardiovascular risk was calculated from age, gender, systolic blood pressure, treatment for hypertension, diabetes mellitus, high density lipoprotein (HDL) and total cholesterol using online calculator and is expressed as percentage.

Statistical analysis
Data were analyzed by univariate analysis using Fisher's exact test.p< 0.05 was considered statistically significant.The variables with statistical significance in the univariate analysis were subjected to multivariate analysis by Cox regression analysis.

Results
NODAT was observed in 32 (26.6%) among 120 renal transplant recipients.We selected 48 patients from the same cohort who were on continuous follow up for at least 1 year for the control group.Mean duration of follow up was 18 ± 6 months and male: female ratio was 2:1 in both groups.The timeline of occurrence of NODAT range from immediate post-transplant period to 18 months.Of the 32 patients, 71.8% developed NODAT within the first 6 months of transplant and 6.25% after 1 year of transplant.Cumulative incidence was highest at the end of 1 year.Details of mean age of the patients, pre and post transplant risk factors of NODAT and complications are given in table 1. Univariate analysis by Fisher's Exact test revealed higher age of the recipients, pre-transplant impaired fasting glucose, family history of diabetes in the first degree relatives and HCV infection as statistically significant risk factor for the development of NODAT.With Cox multivariate regression analysis table 2, higher age of recipients and family history of diabetes were found to be an independent predictor of NODAT with the hazard ratio of 2.3 (CI 1.35 to 3.9) and 3.1 (CI 1.07 to 9.4), respectively.
In the NODAT group, we measured fasting C -peptide level in 18 patients and calculated β cell function and insulin sensitivity by HOMA version 2.2.Out of 18 patients, seven had fasting C-peptide levels in the upper limit of normal range and two had levels above normal (0.9-7 ng/ ml).Only one patient had level below normal.We found a predominant insulin resistance in (11/18) 61% and predominant β cell dysfunction in 16.6% (3/18) and both in 22.2% (4/18) of patients.Overall, 12 out of 18 patients have insulin sensitivity of < 50%.
There was a higher incidence of UTI, other bacterial infections which include tuberculosis and fungal infections (hazard ratio 3.6) in the study group.Of the fungal infections, two patients had cutaneous infection and three patients had systemic infections in the study group, but only one systemic fungal infection in the control group.Though not statistically significant there was a higher incidence of graft dysfunction in the control (20.8%) than study group (12.5%).Two patients died in the study group, one due to sepsis and other due to HCV related decompensated liver disease and one patient developed diabetic ketoacidosis during the study period.In the assessment of long term cardiovascular risk, 37.5% in the study group had Framingham 10 year cardiovascular risk score of more than 10% and none had similar risk in the control.

Discussion
New onset diabetes after renal transplantation remains an Achilles heel in the long-term patient survival in renal transplant recipients.Incidence of NODAT in this study was 26.6% compared to 16-30% in other studies [5,6].The cumulative incidence of NODAT in this study was 8.3%, 19.1% and 25% at 3, 6 and 12 months respectively whereas the USRDS data [4] showed 9.1%, 16% and 24% at 3, 12 and 36 months respectively.Higher cumulative incidence at the end of first post-transplant year in our centre was probably due to the high dose of steroids in the first 6 months after transplantation.
Recipients in the study group were older than the control and higher age was found to be an independent risk factor for NODAT with a hazard ratio of 2.3 (CI 1.35-3.99),comparable with Cosio et al. [7] who showed patients older than 45 years were 2.9 times more likely to develop NODAT.There was no gender predilection for NODAT noted in this study.Family history of diabetes was present in 46.8% in the study group, whereas only 10% in the control group and was found to be an independent risk factor with a hazard ratio of 3.1 ( CI 1.07-9.46)similar to Sumrani et al. [8].
In the meta analysis by Fabrizi et al. [9] HCV seropositive status was associated with 3.75 fold increased risk of NODAT.Anti HCV positivity was present in 34.3% in the study group compared to 10% in the control group, but it was not an independent risk factor.Though most of the studies [10,11] have shown obesity as an important risk factor for NODAT, pre-transplant over weight (BMI >23 kg/m 2 ) and post-transplant weight gain had no influence on NODAT occurence in our patients similar to Sumrani et al .Pre-transplant impaired fasting glucose was found to be an important risk factor for NODAT which was in concordance with Cosio et al. [7] who showed a RR of 1.5 for NODAT in those with pre-transplant fasting plasma glucose >100-110 mg/dl .The incidence of NODAT was found to be higher in patients receiving tacrolimus (74.4%) than cyclosporine (21.6%).The incidence of NODAT in our parients on tacrolimus was very high compared to Western population [4,12].Further studies are needed to show whether  Asians are more prone for tacrolimus induced β cell dysfunction.Steroids as the risk factor for NODAT could not be studied because there was no dose difference between the groups, but 40.6% in the study group had received additional 2500 mg of steroids in the form of anti rejection therapy compared to 23% in the control.
Insulin deficiency due to β cell dysfunction caused by calcineurin inhibitors and insulin resistance due to steroids and genetic factors are the proposed pathogenetic [13,14] mechanisms for NODAT.We found a predominant insulin resistance in 61% and predominant β cell dysfunction in 16.6% of patients.There were no studies to compare this with other population.The most plausible explanation will be, in Asians who have an inherent high risk of type 2 diabetes the predominant mechanism for NODAT may be insulin resistance rather than absolute deficiency.But this needs to be confirmed in large sample size so that the management of NODAT shifts from insulin to insulin sensitizers.Dyslipidemia is the most common metabolic derangement in NODAT [15].Nearly, one third of the study group had hypercholesterolemia, two-third of them had low HDL and three-fourth had statistically significant hypertriglyceridemia.The prevalence of metabolic syndrome was higher in study group (69%) and was a significant risk factor for NODAT.
Higher incidence of UTI [16] and high susceptibility to both cutaneous and systemic fungal infections were noted in the study group.Matas et al. [17] showed an identical graft survival between NODAT and non-NODAT group up to 9 years post-transplant.In this study the higher incidence of graft dysfunction in the control than the study group may be due to the influence of so many factors other than NODAT in the graft function.
Compared to type 2 DM, studies have showed an early occurence and accelerated progression of diabetic complication in NODAT [18][19][20].We assessed the risk of NODAT on long term cardiovascular complications by calculating 10 year cardiovascular risk using Framingham risk score.About 37.5% patients in the study group had a score of >10%, but none in the control had similar risk.Further, NODAT was found to be a significant risk factor with a hazard ratio of 2 (CI 1.15-3.72)for 10 year cardiovascular risk.
NODAT is a potential metabolic complication of renal transplantation.Categorisation of renal recipients according to risk factors for NODAT is necessary to reduce its incidence and further appropriate tailoring of immunosuppression should be done to reduce the influence of drugs on NODAT.To conclude, like type 2 DM, NODAT also needs a holistic approach addressing other risk factors like hypertension and dyslipidemia to prolong the longevity of the patient and renal allograft.

Table 1 :
Analysis of risk factors for NODAT.